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Thursday, June 16, 2016

Presurgery Chemotherapy May Make Advanced Ovarian Cancers Responsive to Immunotherapy

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PHILADELPHIA — Metastatic ovarian cancer patients treated with
chemotherapy prior to surgery had altered immune cells in their tumors,
and specific alterations identified suggest that immunotherapy given
after chemotherapy may help in preventing the cancer from coming back,
according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
“We
are studying a type of ovarian cancer called high-grade serous ovarian
cancer (HGSC), which is quite difficult to treat for two main reasons:
first, it is often detected after it has spread quite extensively in the
body; and second, although the disease can respond well to the first
chemotherapy treatments, it often relapses and becomes more difficult to
treat. Therefore we need to find other treatment options after the
initial treatment is given,” said Frances R. Balkwill, PhD, professor of cancer biology at Barts Cancer Institute in Queen Mary University of London, United Kingdom.
Prior
preclinical research in mice suggests that when chemotherapy destroys
cancer cells, it also stimulates immune cells in the cancer that can
kill cancer cells, explained Balkwill. “We wanted to study whether this
was also true in cancer patients, and whether it occurred with the
chemotherapy used to treat women with ovarian cancer,” she added.
“Our
study showed that chemotherapy altered the immune cells called T cells
that are found in metastatic ovarian cancer samples in a way that
suggested they were better able to fight the cancer after the treatment.
Our research provides evidence that immunotherapy may be more effective
if given straight after chemotherapy,” Balkwill said.
Balkwill
and colleagues collected pre- and post-chemotherapy biopsies and blood
samples from 54 patients with advanced-stage HGSC who underwent
platinum-based neoadjuvant (given prior to surgery) chemotherapy, and
from six patients who underwent surgery without prior chemotherapy.
The
researchers analyzed the samples using immunohistochemistry and RNA
sequencing to study the changes in the tumor immune microenvironment of
patients who received and did not receive chemotherapy, and changes
before and after chemotherapy. Patients were categorized into those who
had a good response and those who had a poor response to chemotherapy,
based on a recently approved chemotherapy response score that correlate
with progression-free and overall survival.
They found that in
patients who received chemotherapy, there was evidence of activation of
certain types of T cells that can fight cancer cells, while the number
of a type of T cell that suppresses the immune system decreased. The
results were more pronounced in those who had a good response to
chemotherapy, compared with those who had a poor response to
chemotherapy.
“Although we found that chemotherapy activated the T
cells, the levels of the protein PD-L1 [to which the immune checkpoint
molecule PD-1 binds to disable T cells and prevent them from recognizing
and destroying the cancer cells] remained the same or increased.
However, immune checkpoint blockade therapies [such as pembrolizumab and
nivolumab] can stop this from happening, so we suggest that immune
checkpoint blockade might be a suitable form of immunotherapy to give to
ovarian cancer patients after chemotherapy,” Balkwill said.
The
team also found that chemotherapy reduced the blood levels of certain
cytokines—inflammatory molecules that promote cancer growth—often back
to normal levels in patients who had a good response to chemotherapy.
“This could help immunotherapies work better,” Balkwill noted.
“The
chemotherapies, carboplatin and paclitaxel, given in our study are also
used to treat many different cancer types. It will, therefore, be very
interesting and potentially promising if similar effects are seen in
other cancer types, such as lung cancer,” she added.
According to
Balkwill, a major limitation of the study was the small sample size,
which also prevented them from analyzing pre- and post-chemotherapy
samples from the same patient in some cases as there was not enough
material.
The study co-authors include Steffen Böhm, MD; Anne Montfort, PhD; Oliver M.T. Pearce, PhD; and Michelle Lockley, MD, PhD.
The
study was funded by Swiss Cancer League, the European Research Council,
Cancer Research U.K., and Barts and the London Charity. Balkwill and
the study co-authors mentioned above declare no conflicts of interest.